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Disclosures: ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT

MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion injury in STEMI patients undergoing primary PCI.

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Disclosures: ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT

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  1. MITOCARE STUDYMulticenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion injury in STEMI patients undergoing primary PCI Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, andFaculty of Medicine, University of Oslo, Norway. MitoCare – HEALTH-F2-2010-261034

  2. Disclosures:ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, andFaculty of Medicine, University of Oslo, Norway.

  3. MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion injury in STEMI patients undergoing primary PCI Rationale: TRO40303 has been shown to reduce infarct size by 50% in rat and mouse models, and to improve LVEF at 24h and 1 month in these models. It has also shown protective effects on human isolated cells.Mechanism: The mitochondrial permeability transition pore is believed to be a promising target for preventing reperfusion injury.TRO40303 has shown to inhibit the opening of this transition pore. Scope and Enrolment Period of the Study:October 2011-September 201310 interventional sites in Denmark, France, Norway, Sweden. MitoCare – HEALTH-F2-2010-261034

  4. Study Design TRO40303 Dose 6 mg /kg, N = 90 Drug/placebo given as IV bolus by large peripheral vein, during PCI, just before balloon inflation. Placebo, N = 90 Hospitalization V1 / D30 Follow-up V0 Inclusion and PCI D1 (24h) D2 (48h) D3-D5 (72h) Echocardiography Safety Assessment Troponin I, CK: at T0 (baseline) , 6h, 12h, 18h, 24h, 36h, 48h and 72h after stenting Cardiac Magnetic Resonance Echocardiography at 720h after stenting MitoCare – HEALTH-F2-2010-261034

  5. Key Inclusion / Exclusion Criteria • Age >18 years old • First time STEMI • Presenting within 6h of onset of chest pain • Clinical decision to treat with PCI • Occlusion / TIMI flow 0-1 in culprit artery before PCI --------------------------------------------------------------------------- • Cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis, previous AMI, angina within 48h before infarction, previous CABG • Atrial fibrillation • Pacemaker MitoCare – HEALTH-F2-2010-261034

  6. Study Flow-Chart 168 patients entered in the eCRF 1 patient did not meet the inclusion criteria 167 patients randomized 81 assigned to Placebo 86 assigned to TRO40303 1 patient did not meet the inclusion criteria 1 patient did not meet the inclusion criteria 80 received Placebo 85 received TRO40303 1 patient had a CABG instead of PCI 1 patient had a dissection of coronary artery 80 underwent PCI 83 underwent PCI Safety Population N=165 1 Adverse Event 5 Lost to follow up 3 Consent withdrawn 1 Death 2 Adverse Event 6 Lost to follow up 0 Consent withdrawn 3 Deaths ITT Population N=163 80 included in the Safety analysis 80 included in the Intent to treat analysis 72 included in the Per Protocol analysis 85 included in the Safety analysis 83 included in the Intent to treat analysis 70 included in the Per Protocol analysis MitoCare – HEALTH-F2-2010-261034

  7. Baseline Characteristics (Median (min-max), N patients or % per group) Anterior/Posterior Infarction: 33/47 31/51 • Baseline characteristics were well-balanced between the two groups except for age which was higher in the TRO40303 group Procedural Characteristics Pain-to-balloon time: 180 min (mean) Door-to-balloon time: 38 min (mean)

  8. Procedural Characteristics Procedural characteristics were well-balanced between the two groups except for unsuccessful reperfusion (Median (min-max), N patients or % per group) MitoCare – HEALTH-F2-2010-261034

  9. Study Results: Co-primary Endpoint • Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163 MitoCare – HEALTH-F2-2010-261034

  10. MRI Endpoints Mixed model of ANCOVA MitoCare – HEALTH-F2-2010-261034

  11. MRI Endpoints

  12. Additional Secondary Endpoint: Echocardiography at D30 Placebo TRO40303 • Data presented as mean +/- SEM • Number patients analysed = 105 for LVEDV; 104 for LVESD; 139 for LVEF MitoCare – HEALTH-F2-2010-261034

  13. Safety No difference in AE’s in both study arms CEC adjudicated SAE’s: Fischer exact Test: P=0.013 MitoCare – HEALTH-F2-2010-261034

  14. MITOCARE - Conclusions • The MITOCARE trial did not show any protective effect of TRO40303 compared to placebo in preventing reperfusion injury in STEMI patients treated with primary PCI • A high standard of care accounted for the relatively small infarct size after primary PCI, leaving little room for improvement • There were more adjudicated events in the TRO40303-group than in the placebo-group • This could partly be explained by the difference in unsuccessful reperfusion between the groups (12.1% in the TRO40303-group versus 6.3% in the placebo-group) • These results combined with the many failures in the field raise a provocative issue: whether reperfusion injury occurs at all in man, and, if it does, whether this type of injury really accounts for a significant part of the remaining infarct MitoCare – HEALTH-F2-2010-261034

  15. Thanks to: MITOCARE Clinical Sites • Aalborg, DK: Svend Eggert Jensen, Jan Ravkilde, Hans-Henrik Tilsted, Bent Raungaard, Jens Aaroe, Anna-Marie Bloch Münster, Ernest-Torben Wilhem Fründ, Carsten Wiberg Simonsen, Charlotte Schmidt Skov, Kasper Villefrance. • Bergen, NO: Jan-Erik Nordrehaug, Erlend Eriksen, Vegard Tuseth, Erik JS Packer, Liv Himle, Marion Birkeland Hammer, Terje H Larsen. • Créteil, FR: Jean-Luc Dubois-Randé, Emmanuel Teiger, Philippe Le Corvoisier, Romain Gallet, Stephane Champagne, Pierre-François Lesault, Barnabas Gellen, Gauthier Mouillet, Dionyssis Pongas, Dalila Bitari, Marianne Lescouzeres, Bourhis Marie-Laure, Jean-François Deux. • Oslo, NO: Sigrun Halvorsen, Trygve Sørdahl Hall, Margido Husvik, Maren Tandsaether, Tone Pedersen, Anette Vold, Pavel Hoffmann. • Lund, SE: David Erlinge, Matthias Götberg, Sasha Koul, Fredrik Scherstén, Jesper van der Pals, Jan Harnek, Gustav Smith, Jasminka Holmqvist, Patrik Gilje, Stefan Jovinge, Mariam B Choudhary, Marcus Carlsson, Ewa Mattsson, Anna Duckert, Gunilla Brolin. • Paris, FR: Nicolas Danchin, Etienne Puymirat, Eric Durand, Salvatore Battaglia, Christian Spaulding, Jean-Yves Pagny, Rahal Saliha, Sylvie Marinier, Mousseaux Elie, Nadège Goudet. • Stavanger, NO: Alf Inge Larsen, Jorunn Nilsen, Stein Ørn, G. Greve. • Marseille, FR: Jean-Louis Bonnet, Marc Lambert, Jacques Quilici, Thomas Cuissier, Pierre-Julien Moro, Fiacchetti Claudine, Alexis Jacquier, Monique Bernard, Frank Kober. • Odense, DK: Henrik Steen Hansen, Mikkel Hougaard, Helle Cappelen, Jens Karstoft. • Marseille, FR: Franck Paganelli, Olfa Helal, Isabelle Bouvin. Additional Contributors / Core Labs / DMSB • Sponsor Chief Medical Officer: Jean-louis Abitbol, Pascal Longlade, Wilfried Hauke, Trophos, Marseille, FR • International Study Coordinator: Carole Perez, Séverine Pitel, Valérie Cuvier,Trophos, Marseille, FR • Data Monitoring Committee: Lars Køber, Tabassome Simon, Alain Leizorovicz. • Safety and Ethics Monitoring Committee :Emmanuelle Rial-Sebbag, Thomas Roche. • Clinical Events Committee: Claes Held, Christopher Varenhorst,  Ziad Hijazi • Statistics and data management: Eric Vicaut, Hélène Rousseau, HôpitalFernandWidal, Paris, FR • Central Biomarker Laboratory and Bio-bank: Huseyin Firat, Firalis, Huningue, FR • Central ECG reading: Peter Clemmensen, Rigshospitalet, Copenhagen, DK • Central MRI reading: Håkan Arheden, Henrik Engstrøm, Magnus Carlsson, Einar Heiberg, IMACOR AB,Lund, SE • eCRF: Gilles Sonou, Mobile Health, Paris, FR

  16. Thank you for your attention

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